A major impediment to more effective cancer treatment is the ability of tumors to acquire resistance to cytotoxic and cytostatic therapeutics, a development that contributes to treatment failures exceeding 90% in patients with metastatic carcinomas (Longley and Johnston, J. Pathol. 205:272-292, 2005). Efforts focused on circumventing cellular survival mechanisms after chemotherapy have defined systems that modulate the import, export or metabolism of drugs by tumor cells (Wang et al., Proc. Natl. Acad. Sci. USA 101:3089-3094, 2004; Schmitt et al., Nat. Med. 6:1029-1035, 2000; Helmrich et al., Ocogene 24:4174-4182, 2005; Redmond et al., Front. Biosci. 13:5138-5154, 2008; Wilson et al., Ann. Oncol. 17(Suppl.10):x315-x324. 2006). Enhanced damage repair and modifications to apoptotic and senescence programs also contribute to de novo or acquired tolerance to anti-neoplastic treatments (Schmitt et al., Nat. Med. 6:1029-1035, 2000; Lee and Schmitt, Curr. Opin. Genet. Dev. 13:90-96, 2003; Sakai et al., Nature 451:1116-1120, 2008). In addition, the finding that ex vivo assays of sensitivity to chemotherapy do not accurately predict responses in vivo indicate that tumor microenvironments also contribute substantially to cellular viability after toxic insults (Kobayashi et al., Proc. Natl. Acad. Sci. USA 90:3294-3298, 1993; Waldman et al., Nat. Med. 3:1034-1036, 1997; Samson et al., J. Clin. Oncol. 22:3618-3630, 2004). For example, cell adhesion to matrix molecules can affect life and death decisions in tumor cells responding to damage (Croix et al., J. Natl. Cancer Inst. 88:1285-1296, 1996; Kerbel, Cancer Metastasis Rev. 20:1-2, 2001; Wang et al., J. Natl. Cancer Inst. 94: 1494-1503, 2002). Further, the spatial organization of tumors relative to the vasculature establishes gradients of drug concentration, oxygenation, acidity and states of cell proliferation, each of which may substantially influence cell survival and the subsequent tumor repopulation kinetics (Kim and Tannnock, Nat. Rev. Cancer 5:516-525, 2005; Tredan et al., J. Natl. Cancer Inst. 99:1441-1454, 2007).
Most cytotoxic agents selectively target cancers by exploiting differential tumor cell characteristics, such as high proliferation rates, hypoxia and genome instability, resulting in a favorable therapeutic index. However, cancer therapies also affect benign cells and can disrupt the normal function and physiology of tissues and organs. To avoid host lethality, most anticancer regimens do not rely on single overwhelming treatment doses: both radiation and chemotherapy are administered at intervals to allow the recovery of vital normal cell types. However, gaps between treatment cycles also allow tumor cells to recover, activate and exploit survival mechanisms and resist subsequent therapeutic insults.
Here it is demonstrated that treatment-associated DNA damage responses in benign cells comprising the tumor microenvironment promote therapy resistance and subsequent tumor progression. Evidence of treatment-induced alterations in tumor stroma is provided that include the expression of a diverse spectrum of secreted cytokines and growth factors. Among these, the present disclosure shows that WNT16B is activated in fibroblasts through NF-κB and promotes an epithelial to mesenchymal transition (EMT) in neoplastic prostate epithelium through paracrine signaling. Further, WNT16B, acting in a cell non-autonomous manner, promotes the survival of cancer cells after cytotoxic therapy. In additional embodiments it is demonstrated that secreted fizzled-related protein 2 (SFRP2), serine peptidase inhibitor (Kazal type 1) (SPINK1), and glial cell derived neurotrophic factor (GDNF) are activated in the tumor microenvironment and are targets for intervention for improving cancer therapeutics. As such, the inventors provide herein methods targeting constituents of the tumor microenvironment in conjunction with conventional cancer therapeutics to enhance treatment responses.